Cysteine dioxygenase 1 is a metabolic liability for non-small cell lung cancer
Yun Pyo Kang,
Laura Torrente,
Aimee Falzone,
Cody M Elkins,
Min Liu,
John M Asara,
Christian C Dibble,
Gina M DeNicola
Affiliations
Yun Pyo Kang
Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Laura Torrente
Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Aimee Falzone
Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Cody M Elkins
Department of Cancer Physiology, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
Min Liu
Proteomics and Metabolomics Core Facility, H Lee Moffitt Cancer Center and Research Institute, Tampa, United States
John M Asara
Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, United States; Department of Medicine, Harvard Medical School, Boston, United States
Christian C Dibble
Department of Pathology and Cancer Center, Beth Israel Deaconess Medical Center, Boston, United States; Department of Pathology, Harvard Medical School, Boston, United States
NRF2 is emerging as a major regulator of cellular metabolism. However, most studies have been performed in cancer cells, where co-occurring mutations and tumor selective pressures complicate the influence of NRF2 on metabolism. Here we use genetically engineered, non-transformed primary murine cells to isolate the most immediate effects of NRF2 on cellular metabolism. We find that NRF2 promotes the accumulation of intracellular cysteine and engages the cysteine homeostatic control mechanism mediated by cysteine dioxygenase 1 (CDO1), which catalyzes the irreversible metabolism of cysteine to cysteine sulfinic acid (CSA). Notably, CDO1 is preferentially silenced by promoter methylation in human non-small cell lung cancers (NSCLC) harboring mutations in KEAP1, the negative regulator of NRF2. CDO1 silencing promotes proliferation of NSCLC by limiting the futile metabolism of cysteine to the wasteful and toxic byproducts CSA and sulfite (SO32-), and depletion of cellular NADPH. Thus, CDO1 is a metabolic liability for NSCLC cells with high intracellular cysteine, particularly NRF2/KEAP1 mutant cells.
